Gamma aminobutyric acid (“GABA”) is a principal inhibitory neurotransmitter in the central nervous system of mammals. GABA regulates neuronal excitability by binding to specific transmembrane receptors (Cl−-channel-coupled GABAA receptors and G-protein-coupled GABAB receptors) resulting in stabilization or hyperpolarization of the resting membrane potential. Attenuation of GABAergic neurotransmission is involved in the pathophysiology of several central nervous system disorders in humans, namely anxiety, epileptic seizures, movement disorders, panic, depression, alcoholism, pain and manic behavior. Numerous GABA analogs have therefore been synthesized and described in the art. Amongst the synthesized GABA analogs, gabapentin, pregabalin, vigabatrin and baclofen have been marketed and used for the treatment of different disorders.
5-methyl-3-aminomethyl-hexanoic acid, called pregabalin, is an analog of GABA that decreases central neuronal excitability by binding to an auxiliary alpha-2-delta subunit of a voltage-gated calcium channel on neurons in the central nervous system. Pregabalin, disclosed in U.S. Pat. Nos. 5,563,175 and 6,197,819, marketed under the name LYRICA® in the U.S. is used in the treatment of peripheral neuropathic pain, epilepsy and generalized anxiety disorder. Pregabalin is also effective at treating chronic pain in disorders such as fibromyalgia and spinal cord injury. U.S. Pat. No. 6,117,906 discloses the use of pregabalin in treating anxiety; U.S. Pat. No. 6,001,876 discloses the use of pregabalin in treating pain; U.S. Pat. No. 6,127,418 discloses the use of pregabalin in treating gastrointestinal damage. PCT Publication WO98/58641 discloses use of pregabalin as an anti-inflammatory agent.
One significant problem of GABA analogs is the formation of toxic impurities such as the corresponding gamma-lactams during synthesis and/or formulation and/or storage. The amino group of GABA analogs reacts with its carboxyl functional group to form lactams. This autodegradation due to the intramolecular condensation between the amino and carboxyl group within the GABA analog molecule to form the corresponding lactam presents serious difficulties in formulating GABA analogs and needs to be minimized for safety reasons. GABA analogs under usual storage conditions and also in the presence of water tend to form the undesirable lactam side product. Many of the excipients that may be used for formulating preparations of GABA analogs tend to react with them with lapse of time to form the corresponding lactams by accelerating the dehydration reaction between the amino group and the carboxyl group within the GABA analog molecule. Further, reaction between a GABA analog and the formulation excipients is further accelerated with the use of water or an organic solvent in manufacturing of a pharmaceutical preparation. Such a degradation of GABA analogs with lapse of time due to the formation of the lactam is ascribed to its chemical structure and developed by the influence of water, irrespective of whether or not GABA analog is in the state of a solution or a solid. In the case of gabapentin, the intramolecular lactam 4-cyclohexylpyrrolidone is considered to be more toxic than gabapentin. The cyclic lactam of Pregabalin (4-isobutyl-pyrrolidin-2-one) is also an undesired side product. Hence controlling and monitoring lactam impurity during development and shelf life of pharmaceutical compositions of GABA analog is an important parameter.
Further, the primary amino-group present in the GABA molecule not only is able to form a lactam-ring but also to react with other reducing carbonyl functions. With excipients such as lactose, pregabalin is also known to form conjugates by undergoing a Maillard reaction. The product of this reaction is a simple glycosylamine, which are a combination of lactose and the amine of pregabalin after net loss of water. About seven degradants identified in formulated pregabalin were determined to be conjugates of pregabalin resulting from Maillard reactions (Reference). Further lactam formation is found to occur with these pregabalin conjugates.
It is therefore desirable to provide pharmaceutical compositions that do not comprise conjugate forming excipients, thereby being essentially free of such conjugates and ensuring stability under storage conditions.
Various attempts have been described in the art to reduce the tendency of GABA analogs to form the corresponding lactam in the bulk material and in final, unit dosage forms and provide stable formulations thereof. U.S. Pat. No. 6,054,482 relates to a method of preparing gabapentin that contains less than 20 ppm of an anion of a mineral acid. Pharmaceutical compositions described consist essentially of: (i) an active ingredient which is gabapentin in the free amino acid, crystalline anhydrous form containing less than 0.5% by weight of its corresponding lactam and less than 20 ppm of an anion of a mineral acid and (ii) one or more pharmaceutically acceptable adjuvants that do not promote conversion of more than 0.2% by weight of the gabapentin to its corresponding lactam form when stored at 25° C. and an atmospheric humidity of 50% for one year selected from the group consisting of hydroxypropylmethylcellulose, polyvinylpyrrolidone, crospovidone, poloxamer 407, poloxamer 188, sodium starch glycolate, copolyvidone, maize starch, cyclodextrine, lactose, talc and copolymers of dimethylamino-methacrylic acid and neutral methacrylic acid ester.
European Patent EP 1077692B1 describes the use of alpha-amino acid as stabilizer in pharmaceutical preparations containing a 4-amino-3-substituted-butanoic acid derivative such as gabapentin or pregabalin thereby preventing lactam formation due to autocondensation within the molecule. European Patent EP1077691B1 relates to formulations of 4-amino-3-substituted-butanoic acid derivative wherein degradation owing to lactam formation during formulation and storage is prevented by blocking the evaporation and movement of small amount of residual water in a solid composition by the use of a humectant as a stabilizer. PCT Publication WO2008/003285 discloses stabilized compositions of pregabalin comprising one or several auxiliary agents such as alkaline earth phosphates or pentites and/or hexites or a polyacrylate and being largely free from saccharides such as lactose and not requiring amino acids for stabilization. PCT Publication WO2005/051384 relates to the use of calcium carbonate as a stabilizing agent in solid pharmaceutical composition of an amino acid such as pregabalin or gabapentin. U.S. Pat. No. 6,488,964 relates to manufacturing coated particles of pregabalin, whose lactam content is less than 0.5% wherein a coating solution of polymethacrylate, aminoethyl methacrylate copolymers and cellulose polymers, alone or as a mixture, in at least one organic solvent is sprayed onto the said particles. U.S. Patent Application 2008/0058420A1 relates to a pharmaceutical composition comprising gabapentin and a mixture of excipients capable of not promoting the conversion of gabapentin into the corresponding lactam impurity, which comprises (i) a sliding agent selected from a calcium salt of weak acid, (ii) a lubricating agent selected from hydrogenated castor oil and glyceryl behenate; and optionally (iii) a diluting agent selected from a monosaccharidic sugar like sorbitol, xylitol, mannitol, fructose, dextrose and erythritol and polysaccharidic derivatives like saccharose, mannitol, isomalt, maltitol, a galactomannan, alginic acid or one of its salts, a pectin, a carageenan and maltodextrin. A composition of gabapentin based on use of three different groups of excipients has been disclosed, but that a specific set of excipient causes stabilization or reduction in conversion of gabapentin into the corresponding lactam impurity has not been discussed. The corresponding lactamic impurity in these compositions is said to not exceed 0.2% by weight of gabapentin after being maintained for 3 months at the storage conditions of 25° C. with 60% of relative humidity, and/or at 30° C. with 65% of relative humidity.
European Patent Application EP1395242A relates to liquid pharmaceutical composition comprising a GABA analog such as gabapentin or pregabalin and one or more polyhydric aliphatic alcohols containing 2 to 6 carbon atoms selected from the group consisting of: glycerol, xylitol, sorbitol, mannitol, and a mixture of glycerol and xylitol, with the composition having a pH of about 5.5 to about 7.0 and containing less than 0.5% by weight of gabapentin lactam or pregabalin lactam, respectively, after storage at 2° C. to 10° C. for 18 months to 2 years. One or more polyhydric alcohols comprise about 25% to about 75% weight/volume of the composition. European Patent Application EP1543831A relates to an aqueous pharmaceutical preparation for oral administration comprising pregabalin dissolved or dispersed in aqueous liquid containing suitable adjuvants, characterized in that the acidity of the pharmaceutical preparation is adjusted to a stable pH-range below 6.5 and above 5.5 and the liquid preparation is preserved by a combination of methyl- and ethyl-parabene in a w/v ratio of 3:1 to 5:1. PCT Publication WO2007/107835 relates to a stable oral liquid formulation comprising GABA analogue and polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol containing 2 to 6 carbon atoms selected from glycerol, xylitol, sorbitol, mannitol and mixture thereof, is equal to or less than 20% weight/volume (w/v) of the composition. The composition is said to have less than 0.5% by weight of the corresponding lactam analogue after storage at about 2° C. to 10° C. for 18 months to 2 years.
In view of the aforesaid, it is necessary to provide pharmaceutical compositions of GABA analogs that are substantially free of any lactam impurities. Though some stabilized pharmaceutical compositions have been disclosed in the art, it is desirable to have compositions of GABA analogs that have excellent storage stability with very minimum lactam formation over the storage period. There further exists a need to have compositions that are not only stable but also have desirable in-vitro dissolution and bioavailability during storage. Further a need also exists to identify excipients that when used in pharmaceutical compositions of GABA analogs prevent or minimize degradation of GABA analogue to the corresponding lactam form.
The present inventors have surprisingly found that a GABA analogue, namely pregabalin, can be formulated in a stable pharmaceutical composition having low levels of—pregabalin lactam, with a disaccharide except for trehalose or higher polyol as a stabilizer. The present invention provides a stabilized pharmaceutical composition of pregabalin whose lactam content is less than about 0.2% by weight preferably less than about 0.15% by weight relative to the weight of pregabalin. The invention provides a process for manufacturing stabilized pharmaceutical compositions of pregabalin whose lactam content by weight relative to the weight of pregabalin is less than about 0.2% by weight, preferably less than about 0.15% by weight relative to the weight of pregabalin.